Coffee consumption and migraine: a population-based study

Although coffee is one of the most consumed caffeinated beverages worldwide, the role of coffee consumption in migraine is controversial. This study examined the relationship between coffee consumption and clinical characteristics in participants with migraine compared to those with non-migraine headache. This cross-sectional study used data from a nationwide survey on headache and sleep. Coffee consumption was classified as no-to-low (< 1 cup/day), moderate (1–2 cups/day), or high (≥ 3 cups/day). Of the 3030 survey participants, 170 (5.6%) and 1,768 (58.3%) were identified as having migraine and non-migraine headache, respectively. Coffee consumption tended to increase in the order of non-headache, non-migraine headache, and migraine (linear-by-linear association, p = 0.011). Although psychiatric comorbidities (depression for migraine and anxiety for non-migraine headache) and stress significantly differed according to coffee consumption, most headache characteristics and accompanying symptoms did not differ among the three groups for participants with migraine and non-migraine headache. Response to acute headache treatment—adjusted for age, sex, depression, anxiety, stress, preventive medication use, and current smoking—was not significantly different by coffee consumption in participants with migraine and non-migraine headache. In conclusion, most headache-related characteristics and acute treatment response did not significantly differ by coffee consumption in migraine and non-migraine headache.


Assessment of coffee consumption
Coffee consumption was assessed through the question, "On average, how much coffee did you drink in the past year?".The participants were asked to select one of the following: (1) do not drink coffee, (2) < 1 cup per week, (3) 1-6 cups per week, (4) 1-2 cups per day, (5) 3-4 cups per day, and (6) ≥ 5 cups per day.The level of coffee consumption was further categorized into no-to-low (< 1 cup per day), moderate (1-2 cups per day), and high (≥ 3 cups per day).

Assessment of acute treatment response
The use of medications during acute headache attacks was determined.The effectiveness and tolerability of the acute headache treatment were assessed using the six-item migraine Treatment Optimization Questionnaire (mTOQ-6), a validated measure developed to assess response to acute treatment in persons with migraine 27 .The mTOQ-6 was composed of six items regarding (1) quick return to function, (2) 2-h pain free, (3) sustained 24-h pain relief, (4) tolerability, (5) comfort in making plans, and (6) perceived control.Respondents were asked to rate the frequency of each item using the response options of (1) never, (2) rarely, (3) less than half the time, and (4) half the time or more.The mTOQ-6 total score ranges from 6 to 24.There is no cut-off value, and higher scores indicate better optimization of acute treatment.

Statistical analyses
Categorical variables were compared using the Pearson's χ 2 test or Fisher's exact test.Linear by linear association was used to find trends for categorical variables.For continuous variables, the Kolmogorov-Smirnov test was performed to confirm the normality of the distribution.Nonparametric tests were used when a variable was not normally distributed in at least one group, and all continuous variables were subjected to nonparametric tests.The Kruskal-Wallis test followed by Bonferroni's post hoc test were conducted to compare age and body mass index (BMI).Monthly headache days, monthly severe headache days, monthly acute medication days, headache intensity (numerical rating scale [NRS], 0-10), headache-related disability (MIDAS), and acute headache treatment response (mTOQ-6) were compared using analysis of covariance (ANCOVA) followed by Bonferroni's post hoc test, as ANCOVA can be used even when the model does not meet parametric assumptions because it is robust to violation of assumptions 28 .Age, sex, and BMI were selected as covariates for ANCOVA for all variables.Anxiety, depression, stress, preventive medication use, and current smoking, which are known to affect acute migraine treatment response, were also adjusted for the mTOQ-6 total scores 27 .The significance level was set at two-sided p-value < 0.05 for all analyses.Results are shown as numbers with percentages for categorical variables and as median with interquartile range (IQR) for continuous variables.Statistical analyses were performed using IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, N.Y., USA).No statistical power calculation was conducted to guide the sample size.

Ethical approval
The institutional review board of Severance Hospital approved the CHASE study protocol (Approval Number 2020-0034-001).The study was conducted according to the principles of the Declaration of Helsinki.All participants volunteered and provided their written informed consent to participate in the research.
Among the 1,768 participants with non-migraine headache, the high coffee consumption group was older (high, 46.0 [39.0-51.0];p < 0.001 vs. no-to-low, 34 ) than those with no-to-low and high coffee consumption.The moderate group also had a lower proportion of participants with stress than the no-to-low group (moderate, 21.9% [186/851]; p = 0.002 vs. no-to-low, 29.5% [188/637]).Other headache-related variables including headache days per month, severe headache days per month, acute medication days per month, NRS for pain intensity, MIDAS, depression, and insomnia did not differ with coffee consumption (Table 3).

Use of acute treatment medications in participants with migraine and non-migraine headache
Among the 170 participants with migraine, 34 (62.7%),70 (84.3%),and 23 (69.7%) participants in the no-to-low, moderate, and high groups, respectively, used acute treatment medications.The proportion of participants that used acute treatment medications was significantly higher in the moderate group than in the no-to-low group (p = 0.013).Nevertheless, there were no significant differences in the proportions of participants who used acute treatment medications between the no-to-low and high groups (p > 0.999) and between the moderate and high groups (p = 0.223).Medication classes used for acute treatment did not differ significantly between the three groups, except for tramadol, which lost significance in post hoc analysis (Table 4).
Among the 1768 participants with non-migraine headache, 304 (47.7%), 453 (53.2%), and 153 (54.6%) participants with no-to-low, moderate, and high coffee consumption, respectively, used acute treatment medications.The proportion of participants using acute treatment medications was not significantly different among the three coffee consumption groups (p = 0.056).The use of acute treatment medication classes did not differ significantly among the three groups, except for the combination analgesic class (Table 4).5).

Discussion
The main findings of this study were as follows: (1) coffee consumption showed an increasing trend in the order of non-headache, non-migraine headache, and migraine; (2) depression and stress decreased with increasing coffee consumption in participants with migraine; (3) most headache-related variables and response to acute headache treatment did not differ significantly according to coffee consumption in either migraine or nonmigraine headache.Based on our findings, we could partially reject our hypothesis that clinical characteristics were significantly different according to coffee consumption in participants with migraine.Several studies have evaluated caffeine consumption in migraine and headache.A large study in the United States (US) involving 25,755 women reported that caffeinated coffee consumption did not differ significantly between individuals with migraine and non-migraine headache 17 , but significantly more coffee was consumed by individuals with non-migraine headache than those without headache.A Norwegian study showed that high caffeine intake (> 540 mg/day) was associated with a modest increase in headache prevalence, but there was no significant association between migraine prevalence and caffeine intake 16 .In contrast, an epidemiologic study in Japan found that individuals with migraine consumed significantly more coffee and tea than individuals without headache in the same community 15 .Our study showed a trend toward higher coffee consumption in the order of participants with non-headache, non-migraine headache, and migraine.One possible explanation for the discrepancy between the present study and studies from the US and Norway is the difference in ethnicity.Although the average daily caffeine consumption of 68 mg in Koreans is lower than that of Americans (186 mg) and Norwegians (426 mg), the average daily caffeine consumption of 262 mg in the Japanese population is similar to that of Americans, suggesting that the higher caffeine consumption in migraine compared to non-migraine headache or non-headache is likely due to ethnic differences 16,18,29,30 .The present study may provide evidence of increased coffee consumption in participants with migraine than those with non-migraine in the Asian population, which was different from the US and Norwegian populations.Differences in socioeconomic status and the method to assess caffeine consumption may be other possible explanations for the discrepancy.
Table 2. Demographic and clinical characteristics of headache according to coffee consumption in participants with migraine.For the p-values, categorical variables were compared using the Pearson's χ 2 test and the continuous variables were assessed using the Kruskal-Wallis test or analysis of covariance adjusted for age, sex, and body index mass.§There was a significant difference between no-to-low coffee consumption and moderate coffee consumption in a post hoc analysis.†There was a significant difference between no-to-low coffee consumption and high coffee consumption in a post hoc analysis.‡There was a significant difference between moderate coffee consumption and high coffee consumption in a post hoc analysis.IQR interquartile range, NRS numerical rating scale, MIDAS migraine disability assessment.www.nature.com/scientificreports/Although caffeine has various effects on migraine, detailed information on the impact of caffeine consumption on the clinical characteristics of migraine is scarce.Two studies from the US reported the association between daily caffeine consumption and CDH and identified that high daily caffeine consumption was significantly associated with an increased risk of CDH 13,14 .One study analyzed the outcome by dividing the groups into daily coffee drinkers and non-drinkers, and the other study divided the groups into high and non-high caffeine consumers.Nevertheless, these studies did not evaluate the relationship between caffeine consumption and clinical characteristics of migraine in detail.The present study evaluated detailed clinical characteristics of migraine including headache days per month, headache characteristics, accompanying symptoms, disability by migraine, comorbidities, and response to acute treatment.In contrast to the two previous studies, we found that there were no significant differences in headache days per month, severe headache days per month, and days with acute medications.The discrepancy may be due to differences in the categorization of coffee consumption.We categorized high coffee consumption as ≥ 3 cups/day and assumed that the average caffeine content in a cup of coffee in Korea is 75 mg.This estimation was based on a previous study that calculated the caffeine content of the most popular types of coffee in Korea, using the caffeine levels specified in the Korea Food Additives Code 31 .Therefore, consuming ≥ 3 cups of coffee per day would result in an intake of ≥ 225 mg of caffeine per day.Among the 33 migraineurs in our study who were classified as high coffee consumers, only one consumed ≥ 5 cups/ day, while the remaining 32 consumed 3-4 cups/day (equivalent to 225-300 mg/day of caffeine).A US study categorized high caffeine consumption as > 287 mg/day, which was the top quartile of caffeine consumption 13 .Therefore, a considerable number of participants with migraine in the high coffee consumption group in our study may be classified as non-high caffeine consumers in the American study, which may have contributed to the difference in results.
Furthermore, it has been suggested that migraine and psychiatric comorbidities are closely intertwined.A review article demonstrated that individuals with migraine were more likely to suffer from psychiatric disorders than the general population, and individuals with migraine who suffer from mood disorders were more likely to be refractory to migraine treatments 32 .Additionally, depression, anxiety, and stress were risk factors for treatment refractoriness and migraine chronification in patients with episodic migraine.On the other hand, several studies have shown a protective role for coffee in depression and anxiety [33][34][35] .Results from a meta-analysis showed that coffee consumption was significantly associated with a lower risk of depression 33 .We also found an association between increased coffee consumption and lower rates of depression and stress in participants with migraine.
As it has been suggested that mood disorders are associated with increased migraine frequency and disability 36 , Table 3. Demographic and clinical characteristics of headache according to coffee consumption in participants with non-migraine headache.For the p-values, categorical variables were compared using the Pearson's χ 2 test and the continuous variables were assessed using the Kruskal-Wallis test or analysis of covariance adjusted for age, sex, and body mass index.§There was a significant difference between no-tolow coffee consumption and moderate coffee consumption in a post hoc analysis.†There was a significant difference between no-to-low coffee consumption and high coffee consumption in a post hoc analysis.‡There was a significant difference between moderate coffee consumption and high coffee consumption in a post hoc analysis.IQR interquartile range, NRS numerical rating scale, MIDAS migraine disability assessment.www.nature.com/scientificreports/and that coffee consumption is inversely associated with mood disorders, it was expected that there would be differences in migraine symptoms based on coffee consumption.However, in this study we observed that most clinical features of migraine did not differ by coffee consumption.This finding might be explained by the balance of beneficial and detrimental effects of caffeine on migraine, including the triggering and relief of migraine.The mechanism of action of caffeine in migraine is not fully understood.It has been reported that caffeine, competes with adenosine, with which it shares a similar structure, for the A1 and A2A adenosine receptors; these two receptors have opposing effects with each other 3,37 .Caffeine inhibits the activation of the trigeminal nerve pain pathway and vasodilation by blocking the A2A receptor.Conversely, by antagonizing the A1 receptor, caffeine promotes nitric oxide production, causing vasodilation and triggering migraine.The beneficial and triggering effects of caffeine on migraine may be related to this dual mechanism of action.Table 4. Prevalence of acute medication use and classes in participants with migraine and non-migraine headache.For the p-values, all categorical variables were compared using the Pearson's χ 2 test or Fisher's exact test.§There was a significant difference between no-to-low coffee consumption and moderate coffee consumption in a post hoc analysis.†There was a significant difference between no-to-low coffee consumption and high coffee consumption in a post hoc analysis.NSAIDs non-steroidal anti-inflammatory drugs, COX-2 cyclooxygenase-2.The present study has several limitations.First, we assessed coffee consumption based on participant selfreported number of coffee cups consumed.However, we did not differentiate between types of the coffee consumed; instead, we assessed consumption solely based on the total number of cups.The amount of caffeine in a cup of coffee varies depending on coffee bean variety and roasting methods, serving size, and coffee type 38 .Therefore, the caffeine intake of two individuals reporting the same number of coffee cups consumed may differ.In addition, we did not assess caffeine ingestion through non-coffee beverages, foods, and other sources.Tea, chocolate, cola, carbonated beverages, and caffeine-containing medications are common sources of caffeine other than coffee.However, in Korea, only about 11% of the daily intake of caffeine is consumed from sources other than coffee 18 .The cup-based coffee consumption in our study was similar to a previous study in Korea (< 1 cup/day: 33.4%, 1-2 cups/day, 43.0%, and > 2 cups/day: 23.5%).Second, although we investigated the relationship between coffee consumption and migraine using data from a large sample size, some subgroup analyses had smaller sample size and did not have sufficient sample power.Third, we categorized coffee consumption as no-to-low, moderate, and high coffee consumption based on the coffee consumption of the Korean general population.However, this classification may not be able to properly identify the impact of high caffeine use in Western countries.Studies from European and American countries reported significant effects of high caffeine consumption in migraine or headache 13,14,16 .However, the average caffeine consumption in Korea was lower than that in American and European countries, making it difficult to see the effect of high-dose caffeine intake in the present study.Only 3.0% of the participants in our study consumed ≥ 5 cups in a day, which was estimated to be ≥ 375 mg of caffeine.Fourth, we did examine additives that are often added to coffee.Common additives in coffee such as milk, sugar, creamer, and artificial sweeteners, may influence the clinical presentation of migraine [39][40][41] .Although many epidemiological studies have not examined the use additives, this is a limitation of the present study.Fifth, this study used a self-reported, web-based questionnaire to assess coffee intake, headache diagnosis, insomnia, psychological status, and other relevant factors.The questionnaire used to diagnose migraine had high sensitivity and specificity 21 .Insomnia and psychological status were assessed using questionnaires with high validity and reliability.However, these self-report measures rely on personal recall, which may be prone to error.Lastly, our study was cross-sectional and could not identify causality.

Conclusions
The present study investigated the relationship between migraine and coffee consumption using data from a nationwide population-based study.Coffee consumption showed an increasing trend in the order of participants with migraine, participants with non-migraine headaches, and those with non-headache.A significant correlation was found between coffee consumption and psychiatric comorbidities in participants with migraine, with higher coffee consumption associated with lower levels of depression and stress.However, most clinical characteristics and response to acute treatment were not significantly different according to coffee consumption in participants with migraine.

Figure 1 .
Figure 1.Flowchart of the participation process in the Circannual Change in Headache and Sleep study.

Figure 2 .
Figure 2. Distribution of coffee consumption according to headache diagnosis.
No-to-low coffee consumption, N = 54 Moderate coffee consumption, N = 83 High coffee consumption, N = 33 p No-to-low coffee consumption, N = 637 Moderate coffee consumption, N = 851 High coffee consumption, N = 280 p

Table 1 .
Sociodemographic characteristics of the survey participants, total Korean population, and cases with migraine and non-migraine headache.CI confidence interval.

Table 5 .
Effect of acute medications according to coffee consumption in participants with migraine and nonmigraine headache.For the p-values, the mTOQ-6 total scores were compared using analysis of covariance adjusted for age, sex, body index mass, anxiety, depression, stress, preventive medication use, and current smoking.*Acute medication use among participants, % mTOQ-6 the 6-item migraine Treatment Optimization Questionnaire, IQR interquartile range.